The goals of this hamartoma research proposal overall are to elucidate the molecular signaling pathways that regulate cell size and growth responses involving the tumor suppressor genes TSC1, TSC2, LKB1, and PTEN, and to identify molecular markers and therapeutictargets. The role of this core is to provide critically necessary pathologic materials and pathologic expertise for the review and interpretation of translationof these findings to human hamartoma specimens. This is critically important, because findings fromcellular and mouse model systems must be validated in human clinical specimens. Although there are several translational studies of this kind reported for TSC, there is a remarkable dearth of such studies for Cowden and Peutz-Jeghers syndromes, which correspond to germline mutation in PTEN and LKB1, respectively. In addition, the studies in TSC are limited in scope. Thus, this core will serve a critical role in the development and interpretation ofimmunohistochemical stains that will confirm and extend findings from in vitro studies to human clinical specimens. This core will also serve an important role in the review of pathology seen in the mouse models developed as part of this program, and will also develop and analyze immunohistochemicalstains on rodent tumors that model various aspects of hamartoma development. Thus, our three aims are: Aim 1.To provide a Human Pathology Core of hamartoma lesions for analysis in collaboration with the Project investigators of this P01. Aim 2. To develop and perform immunohistochemical studies on human hamartoma specimens, to provide clinical translation of tissue culture and mouse model findings. Aim 3. To perform immunohistochemicalstudies on pathology specimens from mouse models of TSC and PJS, and derivative models to be generated in this P01 by Projects 1and 2.